Composite biomaterial including anisometric calcium phosphate reinforcement particles and related methods

ABSTRACT

Composite biomaterials (e.g., for use as orthopedic implants), as well as methods of preparing composite biomaterials, are disclosed. The composite biomaterial includes a matrix (e.g., a continuous phase) comprising a thermoplastic, a calcium phosphate composition that is curable in vivo, or combinations thereof. The composite biomaterial also includes an isometric calcium phosphate reinforcement particles which are dispersed within the matrix.

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] The present application claims the benefit of U.S. applicationNo. 60/179,238, filed on Jan. 31, 2000, which is hereby incorporated inits entirety by reference.

TECHNICAL FIELD OF THE INVENTION

[0002] This invention pertains generally to biomaterials. Moreparticularly, the present invention relates to a composite biomaterialthat can be used, for example, as an orthopedic implant.

BACKGROUND OF THE INVENTION

[0003] Orthopedic implants are used commonly as structuralreinforcements in the human body. By way of example, orthopedic implantsare used to strengthen failed bone (e.g., broken or deteriorating bone),to stiffen compromised vertebrae, or to eliminate painful arthritic ordamaged joints. Most orthopedic implants presently in use involve theextensive use of permanent metal hardware, such as, for example, boneplates and screws and spine cages.

[0004] Despite the enhanced mechanical strength and stiffness associatedwith them, such traditional metallic orthopedic implants requireinvasive surgical techniques which impose a large degree of surgicaltrauma, suffering, and rehabilitation time on patients. As an example,the treatment of hip fractures often requires an incision that is twelveinches or longer. Furthermore, when a stiff metal plate or implant isattached to bone, it tends to “shield” the bone tissue from mechanicalstresses, and, under these conditions, native bone undesirably tends toresorb away.

[0005] Nevertheless, finding suitable alternative biomaterials hasproven to be difficult. Particularly, existing non-metal biomaterialshave not been satisfactory, for example, because they are inadequatewith respect to mechanical properties (e.g., strength). For example.dense ceramics would have similar problems because they are stiff, and,thus, are stress shielding, and they have the additional drawback ofbeing brittle such that they have a lower fracture toughness. Inaddition, non-metal biomaterials, such as, for example, existingpolymeric and porous ceramic biomaterials are significantly inferior tonatural cortical bone in terms of mechanical properties, such as, forexample, elastic modulus, tensile strength, and compressive strength.

[0006] By way of example, one alternative approach to the use of metalsin the field of orthopedics involves minimally invasive orthopedicimplant surgical techniques in which injectable bone glue and fillermaterials are used (e.g., to repair a bone fracture) instead of metalplates and screws and the like. As an example, the “skeletal replacementsystem” (SRS) offered by Norian Corporation (Cupertino Calif.) involvesan injectable cementitious material that cures after injection in thebody (i.e., in vivo). However, the SRS material has proven to beunsatisfactory for many load bearing applications because of itsinferior tensile properties and low fracture toughness.

[0007] In addition, noteworthy among polymeric materials is thepolymethyl methacrylate (PMMA) cement. The PMMA cement also suffers frominsufficient mechanical properties, which. while generally better thanSRS, are still inferior to those of natural cortical bone. In addition,another shortcoming associated with PMMA cement is that a large amountof heat is generated undesirably during the exothermic curing process.The heat generated during the exothermic curing reaction limits thevolume of a bone defect that can be filled inasmuch as a large volume ofbone cement will generate sufficient heat to kill adjacent tissues.Furthermore, PMMA cement also has a tendency to leach out MMA monomerthat can have toxic effects on nearby tissues.

[0008] Accordingly, it will be appreciated from the foregoing that thereexists a need in the art for a biomaterial (e.g., for orthopedicimplants) with desirable biomechanical properties, as well as methods ofpreparing such biomaterials. It is an object of the present invention toprovide such a biomaterial and related methods. These and other objectsand advantages of the present invention, as well as additional inventivefeatures, will be apparent from the description of the inventionprovided herein.

BRIEF SUMMARY OF THE INVENTION

[0009] The present invention provides a composite biomaterial as well asmethods of preparing composite biomaterials. The composite biomaterialincludes anisometric calcium phosphate reinforcement particles that aredispersed within a matrix. The matrix comprises a thermoplastic polymer,a calcium phosphate composition that is curable in vivo (e.g., in amammal), or any combination thereof.

[0010] In another aspect of the present invention, provided is a methodof preparing a composite biomaterial comprising (a) a matrix including acalcium phosphate composition that is curable in vivo and (b)anisometric calcium phosphate reinforcement particles arranged withinthe matrix. The method comprises providing the anisometric calciumphosphate reinforcement particles. The method also includes preparingthe calcium phosphate composition from at least one calcium-containingcompound and at least one phosphate-containing compound. At least one ofthe calcium-containing compound and phosphate-containing compound isderived by a hydrothermal reaction. In addition, the method comprisescombining the anisometric calcium phosphate reinforcement particles withthe calcium phosphate composition or, alternatively, with at least oneof the calcium-containing compound or phosphate-containing compoundprior to formation of the calcium phosphate composition.

[0011] In addition, in another aspect, the present invention provides amethod of preparing a composite biomaterial comprising (a) a matrixincluding a thermoplastic polymer and (b) anisometric calcium phosphatereinforcement particles arranged within the matrix. The method comprisesproviding the anisometric calcium phosphate reinforcement particles andproviding the polymer. The method also includes co-processing thepolymer and the calcium phosphate reinforcement particles to obtain asubstantially uniform mixture thereof. In addition, the method comprisesdeforming and/or densifying the mixture to form the compositebiomaterial.

[0012] The invention may best be understood with reference to theaccompanying drawings and the following detailed description of thepreferred embodiments.

BRIEF DESCRIPTION OF THE DRAWINGS

[0013]FIG. 1 is a schematic representation of a whisker-shapedanisometric reinforcement particle, in accordance with the presentinvention.

[0014]FIG. 2 is a schematic representation of a platelet-shapedanisometric reinforcement particle, in accordance with the presentinvention.

[0015]FIG. 3 is a schematic representation of a cross-section of acomposite biomaterial, illustrating anisometric reinforcement particlesdispersed in a matrix in an aligned manner, in accordance with apreferred embodiment of the present invention.

[0016]FIG. 4A illustrates a scanning election microscopy (SEM)micrograph of conventional calcium hydroxyapatite (HA) powder.

[0017]FIG. 4B illustrates an SEM micrograph of HA whiskers.

[0018]FIG. 4C illustrates an optical micrograph of high densitypolyethylene (HDPE) powder.

[0019]FIG. 5A illustrates x-ray diffraction patterns (XRD) of HAcrystals in a human cortical bone (femoral midshaft) specimen.

[0020]FIG. 5B illustrates XRD patterns for HA crystals in an exemplarysynthetic HDPE-HA composite that includes 30% by volume HA.

[0021]FIG. 6A illustrates Harris texture index measurements of HAcrystals in a human cortical bone (femoral midshaft) specimen.

[0022]FIG. 6B illustrates Harris texture index measurements of HAcrystals in an exemplary synthetic HDPE-HA composite that includes 30%by volume HA.

DETAILED DESCRIPTION OF THE INVENTION

[0023] The present invention is predicated, at least in part, onproviding composite biomaterials that are biocompatible and havedesirable biomechanical properties (e.g., resembling those of naturalbone). The biomaterials include a matrix (e.g., continuous phase orcontinuum) of, for example, a thermoplastic polymer, a calcium phosphatecomposition, or suitable combinations thereof. Significantly, thecomposite biomaterials of the present invention also include calciumphosphate reinforcement particles, which are dispersed within thematrix, in order to provide mechanical reinforcement. In accordance withthe present invention, the calcium phosphate reinforcement particles areeither single crystals or dense polycrystals and are anisometric (asopposed to equiaxed) in nature such that the reinforcement particlesexhibit different properties in different orientations orcrystallographic directions. As a result of the anisometric nature ofthe reinforcement particles, especially if aligned (as discussed hereinbelow), the inventive composite biomaterials possess enhancedbiomechanical properties. The composite biomaterials of the presentinvention have significant utility, for example, in mammalian orthopedicimplants (e.g., as a prosthesis for replacement of bone).

[0024] The matrix can be bioresorbable (i.e., a material capable ofbeing resorbed by a patient, e.g., a mammal, under normal physiologicalconditions) or non-bioresorbable, as desired. In this respect, in someapplications, it is desirable that the biomaterial be bioresorbable bythe patient, such as, for example, in younger patients where boneregeneration occurs readily. Desirably, in some embodiments,bioresorbable materials are selected so as to be tailored to theparticular patient's own bone regeneration process such that thebioresorbable material would be replaced gradually over time by thepatient's own natural (regenerated) tissue.

[0025] In other applications, non-bioresorbability is desirable, e.g.,in older patients where bone regeneration is retarded, so that thebiomaterial remains inert and demonstrates little degradation inbiomechanical properties. However, the decision of whether to use abioresorbable or non-bioresorbable biomaterial depends on many factorsincluding the patient's health profile, the degree of injury, and theprocedure preferred by the surgeon.

[0026] The biomaterial can be percutaneously injected, surgicallyinjected, or surgically implanted, depending upon the material ormaterials selected for the matrix. By way of example, in embodimentswhere a major portion of the matrix is a calcium phosphate compositionor a thermoplastic polymer composition that exhibits flowabilityinitially but is capable of curing (setting up) in vivo in a mammalianhost after some period of time, percutaneous or surgical injection(e.g., via a needle, catheter, glue gun or the like) can be utilized todeliver the inventive biomaterial while in the flowable state to thedesired in vivo location. In other embodiments, the initially flowablecomposition can be cured and formed into a desired shape ex vivo andsurgically implanted. In still other embodiments, for example, where amajor portion of the matrix includes a calcium phosphate composition ora thermoplastic polymer composition where in vivo delivery by injectionand/or curing is not possible or sufficiently limited, the biomaterialcan be appropriately shaped by the surgeon and surgically implanted.

[0027] Any suitable calcium phosphate composition (e.g., cement) orthermoplastic material, as well as suitable combinations thereof, can beincluded in the matrix. By way of example, and not limitation, examplesof suitable calcium phosphate compounds for inclusion (alone or incombination) in the calcium phosphate composition are listed in Table I.In addition, one or more dopants (e.g., sodium, potassium, magnesium,carbonate, fluoride, chloride, and the like) optionally can be includedin the calcium phosphate composition. If included, the dopantspreferably are included in an amount of less than about 10% by weight ofthe calcium phosphate composition. TABLE I Exemplary Calcium PhosphateCompounds Abbrev Chemical Formula Chemical Name Mineral Name ACPCa_(x)(PO₄)_(y) Amorphous calcium phosphate BCP (Ca₁₀(PO₄)₆OH)_(x) +biphasic calcium (Ca₃(PO₄)₆)_(1-x) phosphate CP calcium phosphate DCPCaHPO₄ dicalcium phosphate Monetite DCPD CaHPO₄ · 2H₂O dicalciumphosphate Brushite dihydrate HA or Ca₁₀(PO₄)₆(OH)₂ calcium Apatite orOHAp hydroxyapatite hydroxyapatite CO₃Ap Ca₁₀(PO₄)₆(OH)₂ carbonatedcalcium Carbonate with CO₃'s hydroxyapatite apatite substituting PO₄'sand/or OH's MCP Ca(H₂PO₄)₂ monocalcium phosphate MCPM Ca(H₂(PO₄)₂ · H₂Omonocalcium phosphate monohydrate OCP Ca₈H₂(PO₄)₆ · 5H₂O octacalciumphosphate TCP Ca₃(PO₄)₂ tricalcium phosphate α-TCP α-Ca₃(PO₄)₂alpha-tricalcium phosphate β-TCP β-Ca₃(PO₄)₂ beta-tricalcium phosphateTTCP Ca₄(PO₄)₂O Tetra-calcium Hilgenstockite phosphate

[0028] As will be appreciated by one skilled in the art, thebioresorbability of these calcium phosphate compounds varies accordingto crystal chemistry.

[0029] Referring now to thermoplastic polymers, examples ofbioresorbable thermoplastics include, but are not limited to,poly(DL-lactide) (DLPLA), poly(L-lactide) (LPLA), poly(glycolide) (PGA),poly(ε-caprolactone) (PCL), poly(dioxanone) (PDO), poly(glyconate),poly(hydroxybutyrate) (PHB), poly(hydroxyvalerate (PHV),poly(orthoesters), poly(carboxylates), poly(propylene fumarate),poly(phosphates), poly(carbonates), poly(anhydrides),poly(iminocarbonates), poly(phosphazenes), and the like, as well ascopolymers or blends thereof, and combinations thereof.

[0030] Examples of non-bioresorbable thermoplastics include, but are notlimited to, polyethylenes, such as high density polyethylene (HDPE),ultra high molecular weight polyethylene (UHMWPE), and low densitypolyethylene (LDPE), as well as polybutylene, polystyrene, polyurethane,polypropylene, polyacrylates, polymethacrylates, such aspolymethylmethacrylate (PMMA), and polymerized monomers such astri(ethylene glycol) dimethacrylate (TEG-DMA), bisphenol a hydroxypropylmethacrylate (bis-GMA), and other monomers listed herein below, and thelike, as well as copolymers or blends thereof and combinations thereof.

[0031] In some embodiments, the matrix can include a combination ofcalcium phosphate compounds, a combination of thermoplastics, or acombination of one or more calcium phosphate compounds and one or morethermoplastics. Strictly by way of example, in some embodiments, thematrix can include a combination of at least one non-bioresorbablematerial (e.g., thermoplastic or calcium phosphate) and at least onebioresorbable material. For example, the matrix can include at least onecalcium phosphate compound as well as particulate or dissolved (e.g., inwater or other suitable biocompatible medium) thermoplastic.

[0032] Desirably, in some embodiments in which the matrix includes acombination of a non-bioresorbable material and a bioresorbablematerial, the matrix can be arranged so that the concentration of thebioresorbable component is higher at or near the matrix surface. In thisrespect, the bioresorbable component can be graded from the matrixsurface to the inner core of the matrix.

[0033] With respect to the reinforcement particles, the particularcalcium phosphate utilized for the reinforcement particles can beselected. for example, from the list in Table I, as well as combinationsthereof. Dopants or other additives can be included within thereinforcement particles, if desired. In accordance with the presentinvention, the calcium phosphate reinforcement particles are in the formof single crystals or dense polycrystals, and are anisometric in nature.For example, the calcium phosphate reinforcement particles 10 can be inthe shape of whiskers 12, as shown in FIG. 1, or in the shape ofplatelets 14, as shown in FIG. 2. In particular, the reinforcementparticles are characterized as having a c-axis 16, which is the longestothogonal axis, and an a-axis 18, which is the shortest othogonal axis,as shown in FIGS. 1 and 2. Pursuant to the present invention, inasmuchas the reinforcement particles are anisometric (and not equiaxed), therespective lengths along the c-axis and the a-axis are different. Inthis respect, the reinforcement particles of the present invention arecharacterized as having a mean aspect ratio (length along c-axis/lengthalong a-axis) of greater than 1 and less than 100. Preferably, the meanaspect ratio of the reinforcement particles is from about 5 to about 50,more preferably, from about 7.5 to about 35, and still more preferably,from about 10 to about 20.

[0034] The reinforcement particles can be of any suitable size. Forexample, in some embodiments, the reinforcement particles have meandimensions of from about 1 micrometer to about 500 micrometers along thec-axis and from about 0.02 micrometers to about 20 micrometers along thea-axis. Other exemplary mean dimensions include a length of from about 5micrometers to about 50 micrometers along the c-axis and a length offrom about 0.1 micrometer to about 10 micrometers along the a-axis.Additional exemplary mean dimensions include a length of from about 10micrometers to about 40 micrometers along the c-axis and a length offrom about 0.2 micrometers to about 8 micrometers along the a-axis.

[0035] In addition, some smaller, (e.g., nano-sized) calcium phosphatereinforcement particles can be included as well. For example, thenano-sized (e.g., mean dimensions of from about 1 nanometers to about500 nanometers) can be in the form of bioresorbable particles, in whichcase the smaller size would be advantageous because resorption wouldoccur more readily. Desirably, if present, the nano-sized reinforcementparticles are concentrated more heavily at or near the matrix surface.In particular, if present, the nano-sized calcium phosphatereinforcement particles preferably are graded from the matrix surface tothe inner core of the matrix.

[0036] The reinforcement particles can be included in any suitableamount in the inventive composite biomaterial. For example, thereinforcement particles can be provided in an amount of from about 1% byvolume of the composite biomaterial to about 60% by volume of thecomposite biomaterial, more preferably, from about 30% by volume of thecomposite to about 60% by volume of the composite, still morepreferably, from about 40% by volume of the composite to about 60% byvolume of the composite.

[0037] Notably, the calcium phosphate reinforcement particles providemechanical reinforcement (e.g., strength and/or fracture toughness), forexample, because of their anisometric morphology and because of theirnature as single-crystals or dense polycrystals which have greaterinherent mechanical properties as compared to the matrix. With respectto morphology, because the reinforcement particles geometrically areanisometric, the particles effectively reinforce the biomaterial.Particularly, the anisometric reinforcement particles 10 can be providedso that they are dispersed in the matrix 20, preferably so that there isoverlap between particles, as seen in FIG. 3, so that reinforcement isenhanced. For purposes of clarity, the term “dispersed” does notpreclude some contact between particles.

[0038] The reinforcement particles can be randomly oriented (i.e.,unaligned) in some embodiments. However, as seen in FIG. 3, thereinforcement particles 10 preferably are predominately aligned withinthe matrix 20. Crystallographic or morphological alignment (e.g., apreferred orientation) of the reinforcement particles within the matrix20 results in anisotropy for the overall composite 22. By way ofcontrast, if the reinforcement particles are randomly oriented (i.e., nopreferred orientation) within the matrix, the overall compositepossesses isotropic properties. Composites exhibiting anisotropicproperties, that is, having different properties in different directionsof the composite, possess enhanced mechanical properties in one or twodirections of the composite over composites exhibiting isotropicproperties, that is, having equal properties in all directions, all elsebeing equal. In many cases (for example. the long shaft of the femur),the unique mechanical properties possessed by native human bone are dueto anisotropy.

[0039] As used herein, the term “aligned” reinforcements will beunderstood by those of ordinary skill in the art as a preferredcrystallographic or morphological orientation. The preferred orientationor texture of a material is most accurately measured quantitatively byway of an orientation distribution function (ODF). An ODF can bemeasured using x-ray diffraction pole figure analysis and/orstereological analysis, as described by Sandlin et al., “TextureMeasurement on Materials Containing Platelets Using Stereology,” J. Am.Ceram. Soc., 77 [8] 2127-2131 (1994). In these quantitative techniques,a random ODF is assigned a value of 1, such that values greater than 1indicate a preferred (aligned) orientation in multiples of a randomdistribution (MRD). In accordance with preferred embodiments of theinvention, the reinforcement particles are aligned in the matrix suchthat they have an ODF pursuant to this quantitative technique of greaterthan 1 MRD, more preferably, an ODF of at least about 2 MRD, even morepreferably an ODF of at least about 3 MRD, still more preferably, an ODFof at least about 4 MRD, even more preferably an ODF of at least about 5MRD, e.g., an ODF of from about 5-20 MRD, which approximatelycorresponds to that of the human femur. In some embodiments, it isdesirable to have an even higher ODF, for example, an ODF of at leastabout 20, to achieve mechanical anisotropy in the synthetic compositebiomaterial that matches the host's bone material

[0040] As will be appreciated by those of ordinary skill in the art,semi-quantitative techniques of identifying the preferred (aligned)orientation or texture of a material are described by Harris (see, e.g.,“Quantitative Measurement of Preferred Orientation in Rolled UraniumBars,” Phil. Mag. 43 [336] 113-123 (1952); and Peterson et al., “X-RayTexture Analysis of Oriented PZT Thin Films,” Mat. Res. Joc. Symp.Proc., 433, 297-302 (1996)) and Lotgering (see, e.g., “TopotacticalReactions with Ferrimagnetic Oxides Having Hexagonal CrystalStructures—I,” J. Inorg. Nucl. Chem., 9, 113-123 (1959)). It will beappreciated that under the Harris technique, a random orientation alsois assigned a value of 1, while in the Lotgering technique, the randomorientation is assigned a value of zero. Thus, a preferred, or aligned,orientation would have a volume greater than 1 or zero, respectively,under these semi-quantitative techniques.

[0041] In addition to their morphology, the inherent strength of thereinforcement particles, which is greater than that of the matrix,enhances the mechanical strength of the composite. In this respect,whereas the matrix can include a porous material of polycrystals (e.g.,cement), the reinforcement particles are not porous and are unitarycrystals. The porosity of the matrix is biologically advantageous butundesirable with respect to mechanical strength. Accordingly, thereinforcement particles enhance the mechanical strength of the compositebiomaterial of the present invention.

[0042] The inventive composite biomaterial optionally can includeadditives, if desired. By way of example, the biomaterial can includeone or more surface-active agents in order to enhance interfacialbonding between the reinforcement particles and the matrix. As otherexamples, the inventive biomaterial can include one or more growthfactors, including, but not limited to, those in the TGF-beta superfamily (e.g., TGF-betas, bone morphogenic proteins, such as, forexample, BMP-2, BMP-7 or the like, etc.), fibroblast growth factors,epidermal growth factors, vascular endothelial growth factors,insulin-like growth factors, or interleukins, to enhanceosteoinductivity and/or bone regeneration. Furthermore, the inventivebiomaterial can include one or more transcription factors or matrixmetalloproteinases to improve bone regeneration, or speed resporptionand replacement of the biomaterial. In addition, the biomaterial can becoated with one or more peptides or proteins that enhance attachment ofbone cells (e.g., osteopontin, integrins, matrix receptors, RGD, or thelike).

[0043] The anisometric calcium phosphate particles can be prepared inany suitable manner. Suitable techniques are described, for example, inU.S. Pat. No. 5,227,147; Fujishiro et al., “Preparation of Needle-likeHydroxyapatite by Homogeneous Precipitation under HydrothermalConditions,” J. Chem. Technol. Biotechnol., 57, 349-353 (1993);Yoshimura et al. “Hydrothermal Synthesis of Biocompatible Whiskers,” J.Mater. Sci., 29, 3399-3402 (1994); Suchanek et al., “BiocompatibleWhiskers with Controlled Morphology and Stoichiometry,” J. Mater. Res.,10 [3] 521-529 (1995); Kandori et al., “Texture and Formation Mechanismof Fibrous Calcium Hydroxyapatite Particles Prepared by Decomposition ofCalcium-EDTA Chelates,” J. Am. Ceram. Soc., 80 [5] 1157-1164 (1997);Nakahira et al., “Novel Synthesis Method of Hydroxyapatite Whiskers byHydrolysis of α-Tricalcium Phosphate in Mixtures of Water and OrganicSolvent,” J. Am. Ceram. Soc., 82 [8] 2029-2032 (1999); and Katsuki etal., “Microwave- Versus Conventional-Hydrothermal Synthesis ofHydroxyapatite Crystals from Gypsum,” J. Am. Ceram. Soc., 82 [8]2257-2259 (1999).

[0044] In some embodiments, the reinforcement particles can be producedby way of a hydrothermal reaction, e.g., at low temperatures (such as,for example, from about 37° C. to about 200° C.) from chemical solutionscontaining chemical reactant precursors, pH modifying precursors, and/orchelating acids. In particular, the reactant precursors can be in theform of a calcium-containing compound and a phosphate-containingcompound, both of which are selected such that they exhibit greatersolubility in water than the solubility in water of thecalcium-containing reinforcement particles desired to be produced (e.g.,via precipitation or ion exchange in solution). Examples of suchcalcium-containing compounds include, but are not limited to, thecompounds listed in Table I, as well as calcium hydroxide, calciumnitrate, calcium chloride, calcium carbonate, calcium lactate, calciumacetate, calcium citrate, calcium sulfate, calcium fluoride, calciumoxalate, and the like, as well as combinations thereof. Examples ofphosphate-containing compounds include, but are not limited to, thecompounds listed in Table I, as well as phosphoric acid,fluorophosphoric acid, sodium orthophosphate, potassium orthophosphate,ammonium orthophosphate, and the like, as well as combinations thereof.It will be appreciated that pH modifying precursors can include anysuitable acid or base. Chelating acids can include, for example, formicacid, acetic acid, lactic acid, valeric acid, ethylenediaminetetraceticacid (EDTA), glycolic acid, oxalic acid, citric acid, and the like, aswell as combinations thereof.

[0045] Producing the reinforcement particles hydrothermally is desirablebecause the size and morphology of the resulting reinforcement particlescan be controlled readily, for example, by adjusting the reactantconcentrations solution pH, type of chelating acid, reaction heatingrate, mixing reaction temperature, and length of reaction. Reactiontemperatures, for example, greater than 100° C., are especiallyconducive to whisker formation. It is to be noted, however, thatreactions at temperatures greater than 100° C. require a pressure vesselthat is suitably lined (e.g., with TEFLON®) to contain the pressurizedaqueous solution.

[0046] Turning now to the preparation of the composite biomaterials, amatrix including at least one calcium phosphate composition (that iscurable in vivo) can be prepared from one or more calcium-containing andone or more phosphate-containing reactant compounds. Notably, at leastone of the calcium-containing or phosphate-containing reactant compoundsis derived by a hydrothermal reaction. In some embodiments, both thecalcium-containing and phosphate-containing reactant compounds arederived hydrothermally.

[0047] Particularly, by utilizing a hydrothermal reaction to derive atleast one of the calcium-containing and phosphate-containing reactantcompounds, the resultant reactant compounds can be produced so as tohave a very fine size and controlled purity. Preferably, at least one ofthe calcium-containing and phosphate-containing reactant compounds ischaracterized by particles having a mean diameter of less than about 1micrometer, more preferably, a mean diameter of from about 1 nanometerto about 500 nanometers, even more preferably, from about 1 nanometer toabout 100 nanometers. By starting with a smaller grain size for one orboth of the calcium-containing and phosphate containing reactantcompounds, the resulting calcium phosphate matrix composition also wouldbe in the form of smaller particles (e.g. polycrystals). The smallersize of the particles of the calcium phosphate matrix compositionresults in a matrix of enhanced mechanical strength.

[0048] The calcium-containing and phosphate-containing reactantcompounds can be selected, for example, from the respective lists ofcalcium-containing and phosphate-containing chemical precursorsdiscussed herein above with respect to the reinforcement particles. Toproduce the calcium phosphate matrix composition, the calcium-containingand phosphate-containing reactant compounds can be mixed, for example,while dry (e.g., in powder form). In some embodiments, the powders canbe mixed with phosphoric acid crystals and ground with mortar andpestle. In addition, as an example, a sodium phosphate solution can beadded to form a flowable paste, which is injectable into a patient andwhich is capable of curing in vivo in a mammalian host after injectionat the desired locus (e.g., bone, such as the femur or vertebrae). Inthis respect, the paste desirably is formed, for example, in theoperating room, shortly before delivery (e.g., by injection) into thepatient where it can then harden in vivo. In other embodiments, thecompounds can be prepared in two separate flowable pastes which can bestored separately, and later mixed together and injected at the desiredlocus where it can harden in vivo.

[0049] The calcium phosphate reinforcement particles can be added priorto formation of the calcium phosphate composition (e.g., added to one orboth of the calcium-containing compound(s) and phosphate-containingcompound(s)) and/or after the calcium phosphate composition is formed.

[0050] With respect to the preparation of a composite biomaterialcomprising a matrix that includes at least one thermoplastic polymer, asubstantially uniform mixture of polymer and calcium phosphatereinforcement particles is formed via co-processing. By way of example,in some embodiments, a preform is made from polymer provided in the formof particles. The polymer particles can be produced in any suitablemanner. For example, the polymer can be dissolved in any suitablesolvent in which the polymer can be dissolved (e.g., water, xylene,chloroform, toluene, methylene chloride, tetrahydrofuran, ethyl acetate,hexafluoroisopropanol, acetone, alcohols, and the like). In suchembodiments, the polymer particles can be formed by precipitation orgelation from the solution, for example, under rapid mixing. The solventis then removed, e.g., by vacuum oven drying, distillation andcollection, freeze drying, and the like. Additionally, the polymerparticles and/or gel may be suspended in a suitable medium (e.g., water,alcohols, and the like) and homogenized by high shear mixing to providea uniform distribution of particles or repeatedly washed to removeresidual traces of the solvent. The polymer particles and the calciumphosphate reinforcement particles each are suspended in a suitablemedium for dispersing the particles, (e.g., water, alcohols, and thelike). The preform is then formed by wet co-consolidation of the polymerand calcium phosphate particulate suspension.

[0051] In other embodiments, a preform is formed from a polymer foam,e.g., having open porosity (e.g., continuous). The polymer foam can beprovided in a similar manner to the preparation of the polymerparticles, but while dissolving the polymer at a slower mixing rate,with slower solvent removal, and at a higher fraction of polymerrelative to solvent. Thus, the polymer foam is formed by dissolving thepolymer in solvent (e.g., water, xylene, chloroform, toluene, methylenechloride, tetrahydrofuran, ethyl acetate, hexafluoroisopropanol,acetone, alcohols, and the like) while mixing followed by precipitationor gelation from the solution, followed by solvent removal via vacuumoven drying, distillation and collection, freeze drying, and the like.Additionally, the polymer foam and/or gel may be suspended in a suitablemedium (e.g., water, alcohols, and the like) and repeatedly washed toremove residual traces of the solvent. In these embodiments, theco-processing includes infiltrating the polymer foam with a suspension(e.g., alcohols, in water and the like) of the calcium phosphateparticles, so as to form the preform.

[0052] In still other embodiments, a preform is formed from a porouscompact of the calcium phosphate reinforcement particles. Thethermoplastic polymer is provided and infiltrated into the porouscalcium phosphate compact. By way of example, the polymer can beprovided molten, solvated (e.g., in a biocompatible medium, such aswater or other medium that dissolves the thermoplastic), or as apolymerizing mixture comprising monomer, initiator, and, optionally,polymer powder and/or co-initiators (as discussed herein below). By wayof example, the porous compact of the calcium phosphate reinforcementparticles is produced, for example, by dry pressing the calciumphosphate particles and sintering (e.g., at temperatures of from about600° C. to about 1000° C.) the dry pressed particles to form thecompact. In the co-processing, the porous compact of the calciumphosphate reinforcement particles is infiltrated with the polymer.

[0053] Once the preform is formed, it is thermo-mechanically densifiedand deformed to form the composite biomaterial. By way of example, thepreform can be thermo-mechanically densified and deformed via channeldie forging, injection molding, extrusion, pultrusion, or the like. Inaddition, the thermo-mechanical deformation and densification desirablycan include aligning the calcium phosphate reinforcement particlesmorphologically and/or crystallographically. The composite can bedelivered to the patient, for example, by way of surgical implantation.

[0054] In still further embodiments, where a major portion of the matrixis a thermoplastic polymer composition and the composite biomaterial isto be delivered by either percutaneous or surgical injection, thethermoplastic polymer matrix may also be provided by mixing combinationsof polymer powders and monomers with the addition of initiators andco-initiators (e.g., benzoyl peroxide, dimethylaniline, ascorbic acid,cumene hydroperoxide, tributylborane, sulfinic acid, 4-cyanovalericacid, potassium persulfate, dimethoxybenzoine, benzoic-acid-phenylester,N,N-dimethyl p-toluidine, dihydroxy-ethyl-p-toluidine, and the like, andcombinations thereof) to induce polymerization and hardening in-situduring composite co-processing. Exemplary monomers include, but are notlimited to, acrylic monomers such as, for example, methylmethacrylate(MMA), 2,2′-bis(methacryloylethoxyphenyl) propane (bis-MEEP), bisphenola polyethylene glycol diether dimethacrylate (bis-EMA), urethanedimethacrylate (UDMA), diphenyloxymethacrylate (DPMA),n-butylmethacrylate, tri(ethylene glycol) dimethacrylate (TEG-DMA),bisphenol a hydroxypropylmethacrylate (bis-GMA), and the like, andcombinations thereof. Additionally, stabilizers (e.g., hydroquinone,2-hydroxy-4-methoxy-benzophenone, and the like, and combinationsthereof) may be added to mixtures to prevent premature polymerization ofthe monomers. The calcium phosphate reinforcements may be provided andmixed into any part of the polymer mixture prior to, during or after thepolymer mixture is formed, yielding a flowable, polymerizing compositebiomaterial. Additionally, the polymer and or composite mixture may bemixed under vacuum or centrifuged to minimize porosity caused byentrapped gases. The polymer mixture is viscous in nature and graduallyhardens (or “cures”) as polymerization progresses. Thus, prior tohardening, the composite biomaterial may be shaped and/or delivered bymeans of viscous flow, including such processes as percutaneous orsurgical injection, channel die forging, compression molding, injectionmolding, extrusion, or the like. In addition, mechanical deformationduring viscous flow desirably can include aligning the calcium phosphatereinforcement particles morphologically and/or crystallographically. Oneskilled in the art will recognize that the desired shape of the implantmay be formed ex vivo by mechanical deformation prior to hardening, byshaping or machining a bulk block of the biomaterial after hardening, orby either percutaneous or surgical injection of the biomaterial to thedesired locus where it will harden in vivo.

[0055] The following examples further illustrate the present inventionbut, of course, should not be construed as in any way limiting itsscope.

EXAMPLES 1-4 Exemplary HA Whisker Syntheses

[0056] These examples demonstrate the preparation of exemplary calciumphosphate, namely calcium hydroxyapatite (Ca₁₀(PO₄)₆(OH)₂),reinforcement particles in the shape of “whiskers” with varied size andshape.

[0057] Homogeneous solutions containing 0.01 5M P, 0.025M Ca and 0.050Mchelating acid were prepared. For each solution, 1.725 g of H₃PO₄ and achelating acid were first added to 1000 ml distilled, de-ionized waterunder moderate stirring at room temperature, before dissolving 1.853 gCa(OH)2. The chelating acid was used to chelate Ca ions in solution andincluded one of the following: 5.124 g DL-lactic acid (CH₃CHOHCO₂H),2.302 g formic acid (HCO₂H), 3.003 g glacial acetic acid (CH₃CO₂H), or5.110 g valeric acid (CH₃(CH₂)₃CO₂H), which correspond to examples 1-4,respectively. Each solution was sealed to prevent evaporation andcontinuously stirred until the dissolution of Ca(OH)₂ was determined tobe complete upon visual inspection (typically after 2 h). Solutions werethen filtered, measured for pH, and stored in bottles purged withnitrogen gas. Each solution had pH=4. If necessary, HNO₃ or NH₄OH wereadded to achieve this pH.

[0058] HA whiskers were grown by precipitation from the homogenousreaction solutions in a PTFE-lined stainless steel pressure vessel. Thevessel was filled with a 100 ml aliquot of the reaction solution, purgedwith nitrogen gas, and sealed. The reactor was heated by placing theentire vessel into an oven equilibrated at the desired reactiontemperature. The temperature inside the reactor was measured with timeby a thermocouple placed inside the TEFLON® liner and was shown toasymptotically reached the ambient oven temperature. The reaction washeld at a final temperature of 200° C. for 2 h (8 h total).

[0059] After reaction, the pressure vessel was removed from the oven andcooled to less than 100° C. within 1 h using a water-cooled aluminumblock and motorized fan. Precipitates were filtered from the supernatantsolution using a Büchner funnel and washed under a continuous flow of100 ml distilled, de-ionized water. The filtrate was placed in a petridish and dried in an oven at 80° C. for at least 12 h.

[0060] The precipitate was identified as calcium hydroxyapatite by x-raydiffraction (XRD). The particle dimensions and whisker morphology of theprecipitates was observed by optical microscopy and quantitativelymeasured using stereological techniques (Table 2). TABLE 2 Average Sizeand Shape Measured for the HA Whiskers Synthesized Chelating avg. lengthavg. width avg. aspect Example Acid (μm) (μm) ratio 1 DL-lactic 22.3 2.49.5 acid 2 formic acid 19.3 2.3 8.7 3 acetic acid 25.9 2.5 10.7 4valeric acid 43.1 4.3 11.3

EXAMPLE 5 Exemplary HA-HDPE Composites

[0061] This example demonstrates the preparation of an exemplary highdensity polyethylene (HDPE) matrix reinforced with calcium phosphate,namely calcium hydroxyapatite (Ca₁₀(PO₄)₆(OH)₂), reinforcement particlesin the shape of “whiskers”. For comparison, specimens were made from theHDPE polymer matrix alone as well as the HDPE polymer matrix reinforcedwith a conventional, equiaxed HA powder using the same processingtechnique.

[0062] HA whiskers were grown by precipitation from a homogenous aqueoussolution (similar to example 1), containing 0.05 M Ca(OH)₂, 0.03 MH₃PO₄, and 0.10 M lactic acid, in a TEFLON® lined stainless steelpressure vessel at 200° C. for 4 h. HDPE powder was prepared bydissolving commercially available HDPE pellets in boiling xylene,cooling the solution to form a gel, extracting the solvent, andhomogenizing the precipitated polymer in ethanol.

[0063] The appropriate amounts of HDPE and HA powders wereultrasonically dispersed in ethanol at a solids loading of 13 vol %. Thesuspension was vacuum filtered in a 10 mm diameter mold to form a porouscylindrical composite preform. After drying, the preform wassubsequently pressed in a 10 mm vacuum pellet die to 280 MPa at 25° C.and again at 145° C. Apparent densities of greater than 97% weretypically achieved. The densified preform was then placed verticallyinto a channel die forge and bilaterally extruded at 145° C. into a2.5×10×120 mm flat bar, from which ASTM D638 type V tensile bars weremachined. Tensile tests were performed under atmospheric conditions anda displacement rate of 5 mm/min.

[0064] The degree of preferred crystallographic orientation wasdetermined by x-ray diffraction (XRD). For comparison, human corticalbone specimens were taken from the proximal end of the femoral midshaft.Thick sections were deproteinized by soaking 72 h in 7% NaOCl. TheHarris texture index (see, e.g., Harris and Peterson articles, supra)was used to semi-quantitatively measure the degree of preferredcrystallographic orientation (see discussion herein above).

[0065] The particle size and morphology of all starting powders wereobserved by scanning electron microscopy (SEM), and are shown in FIGS.4A-4C, respectively. The conventional HA (FIG. 4A) was equiaxed andspherical with an average particle size of 2-3 μm. The whiskers (FIG.4B) were on average 20 μm in length with an average aspect ratio of 10.Note that the [002] crystallographic axis lies along the whisker length.The HDPE powder particles (FIG. 4C) were spherical and 10-30 μm indiameter.

[0066] XRD patterns for human cortical bone specimens and an exemplarycomposite are shown in FIGS. 5A and 5B. In both cases, the (002) peakshave a higher relative intensity on the longitudinal cross-sections(second pattern from top) than on the perpendicular cross-sections (thepatterns above and below). Thus, HA crystals in both specimens have apreferred orientation in the longitudinal directions (vertical in theschematics). Harris texture index measurements provided asemi-quantitative estimate the degree of preferred orientation and areshown in FIGS. 6A and 6B. As will be appreciated by those of ordinaryskill in the art, in FIGS. 6A and 6B, “hkl” corresponds to the Millerindices of specific crystallographic planes of the HA reinforcementparticles. It is to be noted that each crystallographic plane listed inFIG. 6 (002, 210, 300) corresponds to a specific XRD peak in FIG. 5. Italso is to be noted that a value of 1.0 corresponds to a randomorientation distribution. Under the given processing conditions, aslightly higher but similar degree of preferred orientation was achievedin the synthetic composite compared to cortical bone. The preferredorientation in bone is known to be physiological in origin. In theHDPE-HA composite, whisker alignment was induced by shear stressesoccurring along the flow field as the material extruded in the forgemold.

[0067] Mechanical tests demonstrated the improved mechanical propertiesof the HA whisker reinforced composites compared to the matrix alone aswell as reinforcement with a conventional HA powder (Table 3). Theenhanced mechanical properties over the conventional HA powder areattributed to the anisometric morphology of the whisker reinforcementsand their preferred orientation (“alignment”) along the direction ofapplied stress. TABLE 3 Mechanical Properties of the Composites inExample 5 Reinforcement Ultimate Tensile Tensile vol % HA Phase Strength(MPa) Modulus (GPa)  0 none 27 1.1 10 conventional 27 2.2 HA 10 HAwhiskers 27 2.5 30 conventional 23 5.3 HA 30 HA whiskers 28 6.5

EXAMPLE 6 Exemplary HA-PMMA Bone Cement Composites

[0068] This example demonstrates the preparation of an exemplarypoly(methylmethacrylate) (PMMA) matrix reinforced with calciumphosphate, namely calcium hydroxyapatite (Ca₁₀(PO₄)₆(OH)₂),reinforcement particles in the shape of “whiskers”. For comparison,specimens were made from the PMMA polymer matrix alone as well as thePMMA polymer matrix reinforced with a conventional, equiaxed HA powderusing the same processing technique.

[0069] HA whiskers were grown by precipitation from a homogenous aqueoussolution (similar to example 1), containing 0.05 M Ca(OH)₂, 0.03 MH₃PO₄, and 0.10 M lactic acid, in a Teflon lined stainless steelpressure vessel at 200° C. for 2 h. A commercially available PMMA bonecement, Simplex P™ (Howmedica), was mixed according to manufacturerrecommendations using a vacuum stirring bowl. However, the monomer andpowder ratios were adjusted to accommodate incorporating varying volumefractions of the HA reinforcements. Prior to reaching the “dough” stage,the bone cements were added to a syringe and injected into ASTM D638type V tensile specimen mold or into ASTM F571 compression specimenmolds. All tests were performed under atmospheric conditions and adisplacement rate of 5 mm/min.

[0070] The particle size and morphology of the HA reinforcement powderswere observed by scanning electron microscopy (SEM), and are shown inFIG. 5. The conventional HA was equiaxed and spherical with an averageparticle size of 2-3 μm. The whiskers were on average 20 μm in lengthwith an average aspect ratio of 10. Note that the [002] crystallographicaxis lies along the whisker length.

[0071] Mechanical tests demonstrated the improved mechanical propertiesof the HA whisker reinforced composites compared to the matrix alone aswell as reinforcement with a conventional HA powder (Table 4). Theenhanced mechanical properties over the conventional HA powder areattributed to the anisometric morphology of the whisker reinforcementsand their preferred orientation (“alignment”) along the direction ofapplied stress. Shear stresses caused by material flow during injectiondeveloped a preferred crystallographic orientation of the HA whiskerswithin the matrix material and yielded anisotropic mechanicalproperties. The degree of preferred orientation in HA whisker reinforcedspecimens, like example 5, was similar to that measured in humancortical bone. TABLE 4 Mechanical Properties of the Composites inExample 6. Ultimate Ultimate Tensile Tensile Compressive vol %Reinforcement Strength Modulus Strength HA Phase (MPa) (GPa) (MPa)  0none 37 3.0 129 10 conventional 23 3.5 117 HA 10 HA whiskers 27 4.3 125

[0072] All of the references cited herein, including patents, patentapplications, and publications, are hereby incorporated in theirentireties by reference.

[0073] While this invention has been described with an emphasis uponpreferred embodiments, it will be obvious to those of ordinary skill inthe art that variations of the preferred embodiments may be used andthat it is intended that the invention may be practiced otherwise thanas specifically described herein. Accordingly, this invention includesall modifications encompassed within the spirit and scope of theinvention as defined by the following claims.

What is claimed is:
 1. A composite biomaterial comprising: (a) a matrixincluding (i) a calcium phosphate composition that can cure in vivo,(ii) a thermoplastic polymer, or (iii) any combination of (i) and/or(ii); and (b) anisometric calcium phosphate reinforcement particlesdispersed within the matrix, wherein the particles are aligned withinthe matrix.
 2. The composite of claim 1, wherein the reinforcementparticles have a mean aspect ratio (length along c-axis/length alonga-axis) of from about 5 to about
 50. 3. The composite of claim 2,wherein the mean aspect ratio is from about 10 to about
 20. 4. Thecomposite of claim 1, wherein at least some of the reinforcementparticles are shaped like whiskers.
 5. The composite of claim 1, whereinat least some of the reinforcement particles are shaped like platelets.6. The composite of claim 1, wherein the reinforcement particles arepresent in an amount of from about 1% by volume of the composite toabout 60% by volume of the composite.
 7. The composite of claim 6,wherein the reinforcement particles are present in an amount of fromabout 40% by volume of the composite to about 60% by volume of thecomposite.
 8. The composite of claim 1, wherein the reinforcementparticles have dimensions of from about 1 micrometer to about 500micrometers along the taxis and from about 0.02 micrometers to about 20micrometers along the a-axis.
 9. The composite of claim 8, wherein thereinforcement particles have a length of from about 5 micrometers toabout 50 micrometers along the c-axis and from about 0.1 micrometers toabout 10 micrometers along the a-axis.
 10. The composite of claim 1,wherein the matrix includes at least one thermoplastic that isnon-bioresorbable.
 11. The composite of claim 10, wherein thenon-bioresorbable thermoplastic is selected from the group consisting ofpolyethylene, high density polyethylene (HDPE), ultra high molecularweight polyethylene (UHMWPE), low density polyethylene (LDPE),polybutylene, polystyrene, polyurethane, polyacrylates,polymethacrylates, polypropylene, copolymers thereof, and blendsthereof.
 12. The composite of claim 1, wherein the matrix includes atleast one thermoplastic that is bioresorbable.
 13. The composite ofclaim 12, wherein the bioresorbable thermoplastic is selected from thegroup consisting of poly(DL-lactide) (DLPLA), poly(L-lactide) (LPLA),poly(glycolide) (PGA), poly(e-caprolactone) (PCL), poly(dioxanone)(PDO), poly(glyconate), poly(hydroxybutyrate) (PHB),poly(hydroxyvalerate (PHV), poly(orthoesters), poly(carboxylates),poly(propylene fumarate), poly(phosphates), poly(carbonates),poly(anhydrides), poly(iminocarbonates), poly(phosphazenes), copolymersor blends thereof, and combinations thereof.
 14. The composite of claim1, wherein the composite includes at least one non-bioresorbablethermoplastic and at least one bioresorbable thermoplastic.
 15. Thecomposite of claim 14, wherein the bioresorbable thermoplastic is gradedfrom a surface of the matrix to an inner core of the matrix.
 16. Thecomposite of claim 1, wherein the matrix includes at least one calciumphosphate compound.
 17. The composite of claim 16, wherein the matrixincludes particulate or dissolved bioresorbable or non-bioresorbablethermoplastic.
 18. The composite of claim 1, wherein at least some ofthe reinforcement particles are bioresorbable.
 19. The composite ofclaim 18, wherein the bioresorbable reinforcement particles are gradedfrom a surface of the matrix to an inner core of the matrix.
 20. Thecomposite of claim 1, wherein the matrix includes the calcium phosphatecomposition, and wherein the calcium phosphate composition is selectedfrom the group consisting of amorphous calcium phosphate, biphasiccalcium phosphate, calcium phosphate, dicalcium phosphate, dicalciumphosphate dihydrate, calcium hydroxyapatite. carbonated calciumhydroxyapatite, monocalcium phosphate, monocalcium phosphatemonohydrate, octacalcium phosphate, tricalcium phosphate,alpha-tricalcium phosphate, beta-tricalcium phosphate, tetracalciumphosphate, and combinations thereof.
 21. The composite of claim 20,wherein the calcium phosphate composition includes at least one dopant.22. The composite of claim 1, wherein the anisometric calcium phosphatereinforcement particles are selected from the group consisting ofamorphous calcium phosphate, biphasic calcium phosphate, calciumphosphate, dicalcium phosphate, dicalcium phosphate dihydrate, calciumhydroxyapatite, carbonated calcium hydroxyapatite, monocalciumphosphate, monocalcium phosphate monohydrate, octacalcium phosphate,tricalcium phosphate, alpha-tricalcium phosphate, beta-tricalciumphosphate, tetracalcium phosphate, and combinations thereof.
 23. Thecomposite of claim 22, wherein at least some of the anisometric calciumphosphate reinforcement particles include at least one dopant.
 24. Thecomposite of claim 1, further comprising at least one surface-activeagent.
 25. The composite of claim 1, further comprising at least oneadditive selected from the group consisting of growth factors,transcription factors, matrix metalloproteinases, peptides, proteins,and combinations thereof.
 26. A prosthesis for replacement of bonecomprising the composite of claim
 1. 27. A method of preparing acomposite biomaterial comprising (a) a matrix including at least onecalcium phosphate composition that can be cured in vivo and (b)anisometric calcium phosphate reinforcement particles arranged withinthe matrix, said method comprising: providing the anisometric calciumphosphate reinforcement particles; preparing the calcium phosphatecomposition from at least one calcium- containing compound and at leastone phosphate-containing compound, wherein at least one of thecalcium-containing compound and phosphate-containing compound is derivedby a hydrothermal reaction; and combining the anisometric calciumphosphate reinforcement particles with the calcium phosphate compositionor with at least one of the calcium-containing compound orphosphate-containing compound prior to formation of the calciumphosphate composition.
 28. The method of claim 27, wherein theanisometric calcium phosphate reinforcement particles are provided via ahydrothermal reaction.
 29. The method of claim 29, wherein at least oneof the calcium-containing compound or phosphate-containing compound isin the form of particles having a mean diameter of less than about 1micrometer.
 30. The method of claim 29, wherein at least one of thecalcium-containing compound or phosphate-containing compound is in theform of particles having a mean diameter of from about 1 nanometers toabout 500 nanometers.
 31. The method of claim 27, wherein each of saidcalcium-containing compound and phosphate-containing compound is derivedby a hydrothermal reaction.
 32. The method of claim 27, wherein theanisometric calcium phosphate reinforcement particles are mixed with atleast one of the calcium-containing compound or phosphate-containingcompound prior to formation of the calcium phosphate composition. 33.The method of claim 27, wherein the anisometric calcium phosphatereinforcement particles are added after the calcium phosphatecomposition is formed.
 34. The method of claim 27, wherein the calciumcontaining compound is selected from the group consisting of calciumhydroxide, calcium nitrate, calcium chloride, calcium carbonate, calciumlactate, calcium acetate, calcium citrate, calcium sulfate, calciumfluoride, calcium oxalate, amorphous calcium phosphate, biphasic calciumphosphate, calcium phosphate, dicalcium phosphate, dicalcium phosphatedihydrate, calcium hydroxyapatite, carbonated calcium hydroxyapatite,monocalcium phosphate, monocalcium phosphate monohydrate, octacalciumphosphate, tricalcium phosphate, alpha-tricalcium phosphate,beta-tricalcium phosphate, tetracalcium phosphate, and combinationsthereof.
 35. The method of claim 27, wherein the phosphate-containingcompound is selected from the group consisting of phosphoric acid,fluorophosphoric acid, sodium orthophosphate, potassium orthophosphate,ammonium orthophosphate, amorphous calcium phosphate, biphasic calciumphosphate, calcium phosphate, dicalcium phosphate, dicalcium phosphatedihydrate, calcium hydroxyapatite, carbonated calcium hydroxyapatite,monocalcium phosphate, monocalcium phosphate monohydrate, octacalciumphosphate, tricalcium phosphate, alpha-tricalcium phosphate,beta-tricalcium phosphate, tetracalcium phosphate, and combinationsthereof.
 36. A method of preparing a composite biomaterial comprising(a) a matrix including at least one thermoplastic polymer and (b)anisometric calcium phosphate reinforcement particles arranged withinthe matrix, said method comprising: providing the anisometric calciumphosphate reinforcement particles; providing the polymer; co-processingthe polymer and the calcium phosphate reinforcement particles to obtaina substantially uniform mixture thereof; and deforming and/or densifyingthe mixture to form the composite biomaterial.
 37. The method of claim36, wherein the anisometric calcium phosphate reinforcement particlesare provided via a hydrothermal reaction.
 38. The method of claim 36,wherein said providing the polymer includes providing particles of thepolymer in a suspension, wherein said providing the anisometric calciumphosphate reinforcement particles includes providing the reinforcementparticles in the suspension or in a second suspension, and wherein saidco-processing includes wet co-consolidation of the calcium phosphatereinforcement particles and the polymer particles to form a preform. 39.The method of claim 38, wherein the polymer particles are produced bydissolving the polymer in a solvent under mixing, followed byprecipitation or gelation of the polymer from the solution, followed bysolvent removal.
 40. The method of claim 39, wherein the solvent removalis by way of vacuum oven drying, distillation and collection, or freezedrying.
 41. The method of claim 36, wherein said providing the polymerincludes providing a foam of polymer having continuous open porosity,and wherein said co-processing includes infiltrating the polymer foamwith a suspension of the calcium phosphate reinforcement particles toform a preform.
 42. The method of claim 41, wherein the polymer foam isproduced by dissolving the polymer in a solvent under mixing, followedby precipitation or gelation of the polymer from the solution, followedby solvent removal.
 43. The method of claim 42, wherein the solventremoval is by way of vacuum oven drying, distillation and collection, orfreeze drying.
 44. The method of claim 36, wherein said providing theanisometric calcium phosphate reinforcement particles includes providinga porous compact of the calcium phosphate reinforcement particles, saidproviding the polymer includes providing a molten or solvated polymer oras a polymerizing mixture comprising monomer and initiator, and,optionally polymer powder, co-initator, and/or stabilizer, and whereinsaid co-processing includes infiltrating the porous compact of thecalcium phosphate reinforcement particles with the polymer.
 45. Themethod of claim 44, wherein the porous compact of the calcium phosphatereinforcement particles is produced by dry pressing calcium phosphateparticles and sintering the dry pressed particles to form the compact.46. The method of claim 45, wherein the sintering is at a temperature offrom about 600° C. to about 1000° C.
 47. The method of claim 36, whereinsaid providing the polymer includes mixing monomer with an initiator,and, optionally, polymer powder and co-initiator, to form apolymer-forming mixture, and wherein said co-processing includespolymerizing and hardening the mixture in situ.
 48. The method of claim47, wherein said initiator and/or co-initiator is selected from thegroup consisting of benzoyl peroxide, dimethylaniline, ascorbic acid,cumene hydroperoxide, tributylborane, sulfinic acid, 4-cyanovalericacid, potassium persulfate, dimethoxybenzoine, benzoic-acid-phenylester,N,N-dimethyl p-toluidine, dihydroxy-ethyl-p-toluidinebenzoyl peroxide,and any combination thereof.
 49. The method of claim 47, wherein saidmonomer is selected from the group consisting of methylmethacrylate(MMA), 2,2′-bis(methacryloylethoxyphenyl) propane (bis-MEEP), bisphenola polyethylene glycol diether dimethacrylate (bis-EMA), urethanedimethacrylate (UDMA), diphenyloxymethacrylate (DPMA),n-butylmethacrylate, tri(ethylene glycol) dimethacrylate (TEG-DMA),bisphenol a hydroxypropylmethacrylate (bis-GMA), and any combinationthereof.
 50. The method of claim 47, wherein said providing the polymerincludes adding a stabilizer to prevent premature polymerization of thepolymer.
 51. The method of claim 50, wherein said stabilizer is selectedfrom hydroquinone, 2-hydroxy-4-methoxy-benzophenone, or combinationsthereof.
 52. The method of claim 47, wherein said co-processingcomprises combining said anisometric calcium phosphate reinforcementparticles with said polymer-forming mixture prior to mixing thecomponents thereof.
 53. The method of claim 47, wherein saidco-processing comprises combining said anisometric calcium phosphatereinforcement particles with said polymer-forming mixture duringpolymerization.
 54. The method of claim 36, wherein the deforming and/ordensifying includes aligning the calcium phosphate reinforcementparticles morphologically and/or crystallographically.
 55. The method ofclaim 36, wherein the deforming and/or densifying occursthermo-mechanically or mechanically.
 56. The method of claim 56, whereinthe thermo-mechanically deforming and/or densifying includes channel dieforging.
 57. The method of claim 56, wherein the thermo-mechanically ormechanically deforming and/or densifying includes compression molding ordie pressing.
 58. The method of claim 56, wherein thethermo-mechanically deforming and/or densifying includes injectionmolding.
 59. The method of claim 56, wherein the thermo-mechanicallydeforming and/or densifying includes extrusion or pultrusion.
 60. Themethod of claim 56, wherein the mechanically deforming and/or densifyingincludes the viscous flow of a molten or polymerizing polymer matrix.61. The method of claim 60, wherein the viscous flow is achieved bypercutaneous or surgical injection, channel die forging, compressionmolding, injection molding, or extrusion.
 62. The method of claim 36,further comprising adding a surface-active agent.